The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy

Michael Lazarou, Danielle A Sliter, Lesley A Kane, Shireen A Sarraf, Chunxin Wang, Jonathon L Burman, Dionisia P Sideris, Adam I Fogel, Richard J Youle

Research output: Contribution to journalArticleResearchpeer-review

941 Citations (Scopus)

Abstract

Protein aggregates and damaged organelles are tagged with ubiquitin chains to trigger selective autophagy. To initiate mitophagy, the ubiquitin kinase PINK1 phosphorylates ubiquitin to activate the ubiquitin ligase parkin, which builds ubiquitin chains on mitochondrial outer membrane proteins, where they act to recruit autophagy receptors. Using genome editing to knockout five autophagy receptors in HeLa cells, here we show that two receptors previously linked to xenophagy, NDP52 and optineurin, are the primary receptors for PINK1- and parkin-mediated mitophagy. PINK1 recruits NDP52 and optineurin, but not p62, to mitochondria to activate mitophagy directly, independently of parkin. Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1, DFCP1 and WIPI1 to focal spots proximal to mitochondria, revealing a function for these autophagy receptors upstream of LC3. This supports a new model in which PINK1-generated phospho-ubiquitin serves as the autophagy signal on mitochondria, and parkin then acts to amplify this signal. This work also suggests direct and broader roles for ubiquitin phosphorylation in other autophagy pathways.
Original languageEnglish
Pages (from-to)309 - 314
Number of pages6
JournalNature
Volume524
Issue number7565
DOIs
Publication statusPublished - 2015

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